Standard therapies for the treatment of human malignancies typically involve the use of chemotherapy or radiation therapy, which function by damaging DNA in both normal and cancerous cells (Lichter, A. S., and Lawrence, T. S. (1995). Recent Advances in Radiation Oncology. N. Engl. J. Med. 332, 371-379). Our growing understanding of this process suggests that the DNA damage response (DDR) functions as part of a complex network controlling many cellular functions, including cell cycle, DNA repair, and various forms of cell death (Harper, J. W., and Elledge, S. J. (2007). The DNA Damage Response: Ten Years After. Mol. Cell 28, 73 745). The DDR is highly interconnected with other progrowth and prodeath signaling networks, which function together to control cell fate in a nonlinear fashion due to multiple levels of feedback and cross-talk. Thus, it is difficult to predict a priori how multiple, often conflicting, signals will be processed by the cell, particularly by malignant cells in which regulatory networks often exist in atypical forms. Predicting the efficacy of treatment and the optimal design of combination therapy will require a detailed understanding of how the DDR and other molecular signals are integrated and processed, how processing is altered by genetic perturbations commonly found in tumors, and how networks can be “rewired” using drugs individually and in combination (Sachs, K., Perez, 0., Pe'er, D., Lauffenburger, D. A., and Nolan, G. P. (2005). Causal protein-signaling networks derived from multiparameter single-cell data. Science 308, 523-529).
In many forms of breast cancer, aberrant hormonal and/or growth factor signaling play key roles in both tumor induction and resistance to treatment (Hanahan, D., and Weinberg, A. A. (2000). The Hallmarks of Cancer Cell 100, 57-70). Moreover, the identification of molecular drivers in specific breast cancer subtypes has led to the development of more efficacious forms of targeted therapy (Schechter, A. L., Stern, D. F., Vaidyanathan, L., Decker, S. J., Drebin, J. A., Greene, M. I., and Weinberg, A. A. (1984). The Neuoncogene: An Erb-B-Related Gene Encoding a 185,000-Mr Tumour Antigen. Nature 312, 513-516.; Slamon, D. J., Clark, G. M., Wong, S. G., Levin, W. J., Ullrich, A., and McGuire, W. L. (1987). Human Breast Cancer: Correlation of Relapse and Survival with Amplification of the HER-2/neuoncogene. Science 235, 177-182). In spite of these advances, there are currently no targeted therapies and no established molecular etiologies for triple-negative breast cancers (TNBC), which are a heterogeneous mix of breast cancers defined only by the absence of estrogen receptor (ER) or progesterone receptor (PR) expression and lack of amplification of the HER2 oncogene (Perou, C. M., Serlie, T., Eisen, M. S., van de Rijn, M., Jeffrey, S. S., Rees, C. A., Pollack, J. R., Ross, D. T., Johnsen, H., Akslen, L. A., et al. (2000). Molecular Portraits of Human Breast Tumours Nature 406, 747-752). Patients with TNBCs have shorter relapse-free survival and a worse overall prognosis than other breast cancer patients; however, they tend to respond, at least initially, to genotoxic chemotherapy (Dent, A., Trudeau, M., Pritchard, K. l., Hanna, W. M., Kahn, H. K., Sawka, C. A., Lickley, L. A., Rawlinson, E., Sun, P., and Narod, S. A. (2007). Triple-Negative Breast Cancer: Clinical Features and Patterns of Recurrence. Clin. Cancer Res. 13, 4429-4434). Triple-negative patients generally do well if pathologic complete response is achieved following chemotherapy. When residual disease exists, however, the prognosis is typically worse than for other breast cancer subtypes (Abeloff, M., Wolff, A., Weber, B., Zaks, T., Sacchini, V., and McCormick, B. (2008). Cancer of the Breast. In Abeloffs Clinical Oncology, M. Abeloff, J. Armitage, J. Niederhuber. M. Kastan, and W. McKenna, ads. (Maryland Heights, Mo.: Churchill Livingstone), pp. 1875-1944). Thus, identifying new strategies to enhance the initial chemosensitivity of TNBC cells may have substantial therapeutic benefit.